苦豆碱通过抑制cGAS-STING通路减轻顺铂诱导的急性肾损伤的机制研究OA

Objective To elucidate the nephroprotective mechanism of aloperine via the cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING)pathway.Methods Eighteen 8-week-old male specific pathogen-free(SPF)C57BL/6 mice were randomly assigned to control,model,and aloperine-treated groups.Except for the control group,acute kidney injury(AKI)was induced by a single intraperitoneal injection of cisplatin.After 3 days of continuous drug administration,mice were euthanized.Kidney tissues were collected for HE staining to assess histological injury scores.Flow cytometry(FCW)was employed to evaluate renal immune cell infiltra-tion and activation.Western blot(WB)and quantitative real-time polymerase chain reaction(qPCR)were performed on kidney homog-enates.Immunofluorescence(IF)was conducted to determine the subcellular localization of IRF3.Results Compared with the control group,the model group exhibited a significantly higher kidney injury score(P<0.0001)and increased infiltration of inflammatory mac-rophages.The mRNA levels of IL-6,IFN-β,CXCL10,cGAS,and STING were significantly upregulated in the model group(all P<0.05).The phosphorylation levels of TBK1 and IRF3 proteins were elevated(P<0.001 and P<0.0001,respectively),accompanied by enhanced nuclear translocation of IRF3(P<0.0001).Compared with the model group,aloperine treatment significantly attenuated the cisplatin-induced increases in kidney injury score,macrophage infiltration,pro-inflammatory cytokine transcription,expression of STING protein,and phosphorylation of TBK1 and IRF3.Conclusion Aloperine alleviates cisplatin-induced acute kidney injury,poten-tially by functioning as a natural antagonist of the STING signaling pathway.